SUMMARY:

The terms ‘hereditary’ and ‘familial’ are sometimes used interchangeably, but are two different concepts

• ‘Hereditary’ is most commonly used when referring to diseases with a known genetic cause
• ’Familial’ disorders are those which appear to have a genetic component, affecting more family members than would be expected by chance alone
  • However, a single genetic cause or explanation is not known

Hereditary Disease

• Generally single gene disorders can often, but not always, be confirmed by a genetic test
• Certain genetic diseases can be identified based upon clinical diagnosis alone, without genetic testing or even evaluation of a family history
  • For example, Marfan syndrome (see ‘Learn More – Primary Sources’ below) is an example where a diagnosis can be made based on meeting certain clinical criteria
• If a genetic cause is found
  • Cascade testing can be helpful, where members who are seemingly unaffected by disease can also be tested to determine if they are at risk for future disease development (see ‘Related ObG Entries’ below)

Familial Disease

• Usually occurs in more individuals in a family than expected by chance
• Genetic and environmental factors coupled with family history play a role in determining the individuals’ risk
  • For example: An individual presents with high blood pressure and heart disease with a father who had an MI at age 65 | While there are single gene disorders associated with CVD, in the majority of cases this scenario would be considered familial | Note that other important behavioral factors along with family history would impact risk and outcomes (e.g., sedentary lifestyle and high fat diet)  

Important Concepts that Can Make Differentiating Between Familial and Hereditary Disorders More Challenging

• Variable expressivity: a single gene disorder may present differently in multiple family members
  • In the case of a pathogenic variant in BRCA1, one woman might develop breast cancer at 45, while her brother develops prostate cancer at 72, even though both siblings carry the same exact mutation
• Reduced Penetrance: a person is known to carry a genetic mutation (either through a genetic test or they are an obligate carrier of the mutation) but they do not exhibit symptoms of that disease
  • In the case of BRCA1: the father of the children above, carries the pathogenic BRCA1 variant – but he is 85 and never developed cancer

Note: When inheritance patterns are clear cut (e.g. autosomal dominant pattern with multiple affected family members), determining that a disorder is hereditary and likely due a significant pathogenic variant is easier | Unfortunately, variable expressivity and reduced penetrance can complicate the presentation | Genetic expertise can be helpful for pedigree analysis to distinguish between familial and hereditary disease and potential risks  

Differentiating Between Hereditary or Familial Disease

• Determining whether a disorder is hereditary requires a detailed evaluation of family history
  • Review by a trained genetics professional with careful attention to detail can be helpful
  • Typically includes a three-generation pedigree with ages of diagnoses
• Genetic testing is an important way to determine if a disease is ‘Hereditary’ or ‘Familial’
  • Known pathogenic variant is identified: Disease considered ‘hereditary’
  • No pathogenic variant identified, yet a strong family history of disease is present: Disease considered ‘familial’ (unless a genetic/hereditary diagnosis can be made based on clinical features alone)

KEY POINTS:

• Many disorders have an important genetic component, but are not caused by a known inherited change in a particular gene
• When counseling patients, the following are potential reasons that a disorder can appear to be tracking more frequently within a family but no definitive genetic answer has yet been found
  • The causative gene has not yet been discovered
  • Perhaps numerous genes and environmental factors are leading to the familial risk
  • Perhaps our current technology cannot uncover the genetic mutation underlying the condition
• Knowing that a condition runs in a family, whether hereditary or familial, can help individuals make proactive lifestyle decisions, in the hopes that it will reduce their risk for disease
  • For example, there are prophylactic surgeries that may be offered women with BRCA pathogenic variants such as risk reducing mastectomy (see ‘Learn More – Primary Sources’ below)
  • Generally, hereditary disorders will carry higher risk for family members and offspring (e.g., carriers of BRCA pathogenic variants vs those with some affected relatives, but no known mutations)
• It can still be helpful to know if a condition is familial because there may be differences in medical recommendations for the patient and family
  • For example, the Gail Calculator considers family history in assessing a woman’s 5-year and lifetime risk for breast cancer and can inform whether risk reducing medications (e.g., raloxifene) should be offered (see ‘Learn More – Primary Sources’ below)
• Referral to a genetic counselor can be very helpful to distinguish between familial or hereditary disease

Learn More – Primary Sources:

ACOG Committee Opinion 478: Family History as a Risk Assessment Tool

Children’s Wisconsin: Multifactorial inheritance

Medline Plus: What is Heritability?

Medline Plus: What are Multifactorial Disorders?

Related ObG Topics:

Cascade Testing: Notifying and Counseling Relatives of Individuals who are BRCA Mutation Carriers

BRCA1 & BRCA2 Mutations: What Are the Risks for Developing Breast and Ovarian Cancer?

What Do You Really Need to Know About Your Patient’s Family History?

Professional Recommendations for Use of Pharmacologic Interventions to Reduce Breast Cancer Risk

Prophylactic Mastectomy and BRCA – Risk Reduction and Guidelines

Marfan Syndrome: a Reportable ACMG Secondary Finding